Project Summary/Abstract Women are twice as likely as men to develop PTSD, even when controlling for amount and type of trauma exposure. This suggests that some gender-specific factor may differentially predispose men and women to PTSD. The estrogen system could contribute to the discrepancy in prevalence of PTSD among men and women, as the estrogen system is organized in a sex-specific manner and is associated with learning, memory, emotional behavior, and psychopathology. In support of this hypothesis, data from a large-scale genetics study demonstrate an association between a single-nucleotide polymorphism (SNP), rs2267735, in a putative estrogen response element (ERE) within ADCYAP1R1 (adenylate cyclase activating polypeptide 1 receptor type 1, ?PAC1?) and PTSD in women, but not in men. Aside from this study, however, little research investigating an interaction between the estrogen system and PTSD has been conducted, although a few studies observe an association between low estradiol, poor fear extinction, and increased psychological symptoms in women with PTSD. More studies have been conducted using healthy human participants and rodent models. These studies also suggest that low estradiol is associated with poor fear extinction and increased intrusive memories. Although the data are suggestive, these studies have largely been conducted in female only cohorts, though men also synthesize estrogens. Furthermore, these studies have been conducted at one time point after development of PTSD, limiting the interpretation of whether the estrogen system confers vulnerability or is altered in the aftermath of PTSD. The proposed study seeks to clarify whether the estrogen system is associated with PTSD and, further, whether the estrogen system is associated with PTSD in a gender-specific manner by assaying estrogen levels, including estradiol and estrone, in both women and men at the time of trauma, after development of PTSD, and with PTSD remission in response to behavioral therapy. We will primarily employ immunoassay to measure plasma and salivary estradiol and estrone concentrations. We will use clinical data to determine whether estradiol and estrone are altered with pathophysiology of PTSD, or whether variation in estradiol and estrone increase risk for PTSD in the face of trauma. The results of the proposed experiments will be critical in determining whether variation in components of the estrogen system is associated with PTSD. Identifying an association between the estrogen system and PTSD could augment our ability to understand the etiology of, diagnose, and, potentially, treat PTSD.